PROJECT SUMMARY/ABSTRACT Genome-wide association studies (GWAS) involves scanning dense genotype markers across the genomes to find genetic variations associated with a particular phenotype. While they are more commonly used in case/control designs to find variants associated with a disease, the phenotypes can be quantitative, and can be used to understand genetic basis phenotypic variation. There are now five GWAS that tried to find genes responsible for the normal facial variation in multiple different human populations. For a complex trait like a facial shape, findings of these studies have been somewhat underwhelming. Each study appears to identify unique sets of genes, and only PAX3 has been replicated in multiple studies. Some of the differences might be due to differences in how phenotypes were quantified and the statistical analysis employed. Potentially more concerning is the lack of tissue specificity of what is exactly being measured in these studies. Traditional sets of anatomical landmarks on human face cluster around eyes, nose, and mouth. While these landmarks are selected for their repeatability and ease of capture, by nature they are on regions that will be impacted by muscle tone and innervation, amount of fat, age, and facial expression, all of which has substantial environmental noise associated with them. While there is no question facial shape is largely determined genetically, the signal may be lost in the current measured phenotype in human facial GWAS. Here we propose to evaluate a potentially untapped resource, diverse set of inbred strains of mice, to conduct quantitative GWAS for craniofacial shape. Phenotypes in inbred strains are stable and reproducible, they are genetically uniform and as such their genotypes are publicly available, negating the need for expensive genotyping individually. The impact of age and other environmental factors on the phenotype are also minimized in inbred models. Our pilot with 32 inbred strains and 10 F1 crosses showed multiple loci (14) exceeding the significance threshold with standard univariate mapping. Based on the results of the pilot we request funds to conduct a more extensive association study using all commercially available inbred strains with dense genotyping and multivariate association mapping. Doing a GWAS on a model organism is still relevant to the human studies, most of which turn to mouse models to further evaluate the involvement of their candidate genes in the phenotype. Any overlapping finding between mouse and human GWA will confirm the contribution of that locus to the phenotype in humans. Identification of novel gene variants can also potentially influence the direction of the future studies in humans.